Blockade of VLA4 sensitizes leukemic and myeloma tumor cells to CD3 redirection in the bone marrow microenvironment

• Published in: Blood cancer journal (New York) Vol. 10; no. 6; p. 65
• Main Authors: Nair-Gupta, Priyanka, Rudnick, Stephen I., Luistro, Leopoldo, Smith, Melissa, McDaid, Ronan, Li, Yingzhe, Pillarisetti, Kodandaram, Joseph, Jocelin, Heidrich, Bradley, Packman, Kathryn, Attar, Ricardo, Gaudet, François
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2020; Springer Nature B.V
• Subjects: 13/106; 13/31; 14/1; 14/63; 631/67/327; 631/67/580; 64/60; Animals; Antibodies, Bispecific - pharmacology; Antibodies, Bispecific - therapeutic use; Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; B-Cell Maturation Antigen - antagonists & inhibitors; B-Cell Maturation Antigen - immunology; Biomedical and Life Sciences; Biomedicine; Bone marrow; Bone Marrow - drug effects; Bone Marrow - immunology; Bone Marrow - pathology; Cancer; Cancer Research; CD3 Complex - antagonists & inhibitors; CD3 Complex - immunology; Cell Line, Tumor; Cytotoxicity; Female; Hematology; Humans; Integrin alpha4beta1 - antagonists & inhibitors; Integrin alpha4beta1 - immunology; Interleukin-3 Receptor alpha Subunit - antagonists & inhibitors; Interleukin-3 Receptor alpha Subunit - immunology; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - immunology; Leukemia, Myeloid, Acute - pathology; Lymphocytes; Mice; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - immunology; Multiple Myeloma - pathology; Oncology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - pathology; Tumor Microenvironment - drug effects
• ISSN: 2044-5385; 2044-5385
• DOI: 10.1038/s41408-020-0331-4

Redirecting T cells to specifically kill malignant cells has been validated as an effective anti-cancer strategy in the clinic with the approval of blinatumomab for acute lymphoblastic leukemia. However, the immunosuppressive nature of the tumor microenvironment potentially poses a significant hurdle to T cell therapies. In hematological malignancies, the bone marrow (BM) niche is protective to leukemic stem cells and has minimized the efficacy of several anti-cancer drugs. In this study, we investigated the impact of the BM microenvironment on T cell redirection. Using bispecific antibodies targeting specific tumor antigens (CD123 and BCMA) and CD3, we observed that co-culture of acute myeloid leukemia or multiple myeloma cells with BM stromal cells protected tumor cells from bispecific antibody-T cell-mediated lysis in vitro and in vivo. Impaired CD3 redirection cytotoxicity was correlated with reduced T cell effector responses and cell–cell contact with stromal cells was implicated in reducing T cell activation and conferring protection of cancer cells. Finally, blocking the VLA4 adhesion pathway in combination with CD3 redirection reduced the stromal-mediated inhibition of cytotoxicity and T cell activation. Our results lend support to inhibiting VLA4 interactions along with administering CD3 redirection therapeutics as a novel combinatorial regimen for robust anti-cancer responses.